Human immunodeficiency virus (HIV) which causes AIDS produces precursor proteins such as a reverse transcriptase or Gag protein used for production of the virus particles in host cells. These precursor proteins can exhibit their functions only when cut into a specific size by a protease of a virus origin (HIV protease). The HIV protease inhibitor which blocks formation and growth of infectious virus particles by inhibiting the enzymatic activity of the HIV protease can be used as an anti-virus agent. Several HIV protease inhibitors have already been reported. One of them is a transition state mimetic which is a compound something like a synthetic peptide (see, for example, T. Robins, J. Plattner, J. Acquir. Immun. Defic. Syndr., 6, 162 (1993)). For example, a hydroxyethylamine derivative such as Ro31-8959 (N. A. Roberts et al., Science 248, 358-361 (1990)) which contains a phenylalanine .phi.[CH(OH)CH.sub.2 N] decahydroisoquinolinecarboxylic acid skeleton similar to an amino acid sequence which is selectively cleaved by an HIV protease, such as -Tyr . . . Pro or -Phe . . . Pro, and a hydroxymethylcarboxamide derivative such as a peptide derivative including a norstati skeleton such as phenylalanine .phi.[CH(OH)C(O)N]proline (T. F. Tam et al., J. Med. Chem. 35, 1318-1320 (1992)) are useful as an HIV protease inhibitor. Clinical application of these substances is being actively promoted.
Specifically, like a transition state mimetic these compounds utilize an HIV protease inhibition activity to control production of the virus particles in host cells, whereby growth and infection of HIV can be controlled and AIDS can be prevented. Clinical application of these compounds as the anti-AIDS medicines is being adopted (Nakajima et al., The Pharmaceuticals monthly, Vol. 35, 2983-2989 (1993)). These transition state mimetics are expected to become next generation anti-AIDS medicines succeeding nucleic acid derivative-type reverse transcriptase inhibitors such as AZT (azidothymidine), DDC (dideoxycytidine), and DDI (dideoxyinosine) which are already clinically used as anti-AIDS drugs.
The present inventors have also discovered that a group of synthetic peptide compounds which are transition state mimetics including a 3-amino-2-hydroxy-4-phenylbutanoic acid residue exhibit a strong HIV protease inhibitive action and are useful as anti-AIDS medicines. The inventors have filed a patent application relating to the HIV protease inhibitor (Japanese Patent Application Laid-open No. 170722/1993). The inventors of the present invention continued the studies in which the inventors have synthesized various peptide compounds and determined chemical structures of novel compounds, including novel compounds exhibiting superior inhibition activity against HIV protease (Japanese Patent Application Laid-open No. 185631/1996, European Patent Publication EP 751145 A2).
However, hydroxymethylcarboxamide derivatives having superior HIV protease inhibition activity among these peptide-type compounds require a comparatively high dose to clinically exhibit a certain effect in many cases. Because anti-AIDS medicines are continuously administered for a long period of time, development of a compound possessing a high HIV protease inhibition activity which can provide a certain effect by oral administration at a small dose is desired. Specifically, development of a compound possessing a novel structure which is capable of tightly binding with HIV protease and exhibits a high treatment effect at a lower plasma concentration is desired.